17alpha-aza-d-homosteroid(17 17a-e)tetrazoles

ABSTRACT

17A-AZA-D-HOMOSTEROID(17,17A-E)TETRAZOLES OF THE ESTRANE AND ANDROSTANE SERIES EXHIBIT ESTROGENIC ORANABOLIC ACTIVITY.

United States Patent Oifice 3,644,367 Patented Feb. 22, 1972 3,644,36717a-AZA-D-HOMOSTEROID[17,17a-e1TETRAZOLES George Rosenkranz and PierreCrabb, Mexico City,

Mexico, assignors to Syntex Corporation, Panama, Republic of Panama NoDrawing. Filed Apr. 30, 1968, Ser. No. 725,536 Int. Cl. C07d /00 US. Cl.260287 R 6 Claims ABSTRACT OF THE DISCLOSURE ;17a-azaD-homosteroid[17,17a-e]tetrazoles of the estrane and androstane seriesexhibit estrogenic or anabolic activity.

The present invention relates to novel pentacyclic steroid tetrazolesand to processes for their preparation.

In particular, the present invention is directed to 17aaza-D-homoestrano17,17a-e1tetrazoles, 17a-aza-D-homoandrostano 17,17a-e] tetrazoles,derivatives thereof, and processes for their preparation.

The present novel !17a-aza-D-homosteroid[17,17a-e] tetrazoles can beillustrated by the following formulas:

1L I l 1% I 1 s R g 4 wherein R is O or the group in which R ishydrogen, hydroxy, alkoxy, tetrahydrofuran-2- yloxy,tetrahydropyran-'2'-yloxy, or a conventional hydrolyzable ester;

R is hydrogen or methyl;

R is hydroxy, alkoxy, tetrahydrofuran-2-yloxy, tetrahydropyran-2'-yloxy,or a conventional hydrolyzable ester; and

Z is a carbon-carbon single bond or a carbon-carbon double bond.

The present novel compounds of Formula I wherein R is methyl are 17a azaD-homoandrostano[17,17a-e] tetrazole derivatives. The novel compounds ofFormula I wherein R is hydrogen are 17a aza D homoestrano-[17,17a-e1tetrazole derivatives. The new steroids of Formula II are 17aaza D homoestra 1,3,5(10) trieno- 17,-17a-e1tetrazole derivatives.

By the term alkoxy is meant alkyl ethers of from 1 to 8 carbon atoms.These alkyl ethers can be straight chain, branch chain or cyclic alkylethers. Accordingly, alkoxy includes methoxy, ethoxy, propoxy,isopropoxy, butoxy, hexoxy, 2-pentoxy, cyclopentoxy, cyclohexoxy, andthe like.

The term conventional hydrolyzable ester as used herein denotes thosehydrolyzable ester groups conventionally employed in the steroid art,preferably those derived from hydrocarbon carboxylic acids and theirsalts. The term hydrocarbon carboxylic acid defines both substituted andunsubstituted hydrocarbon carboxylic acids. These acids can becompletely saturated or possess varying degrees of unsaturation(including aromatic), can

be of straight chain, branch chain, or cyclic structure, and preferablycontain from one to 12 carbon atoms. In addition, they can besubstituted by functional groups, for example, hydroxy, alkoxycontaining up to six carbon atoms, acyloxy containing up to @12 carbonatoms, nitro, amino, halogeno, and the like, attached to the hydrocarbonbackbone chain. Typical conventional hydrolyzable esters thus includedwithin the scope of the term and the instant invention are acetate,propionate, butyrate, valerate, caproate, enanthate, caprylate,pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate,phenylacetate diphenylacetate, diethylacetate, trimethylacetate,tbutylacetate, trimethylhexanoate, methylneopentylacetate,cyclohexylacetate, cyclopentylpropionate, adamantoate, glycolate,methoxyacetate, hemisuccinate, hemiadipate, hemi 5,5 dimethylglutarate,acetoxyacetate, 2-chloro-4- nitrobenzoate, arnin'oacetate,diethylaminoacetate, piperidinoacetate, fi-chloropropionate,trichlorcacetate, p-chlorobutyrate, and the like.

The present novel steroids of Formula I, wherein R is methyl, exhibitanabolic activity and have a high anabolic to androgenic activity ratio.Accordingly, the present compounds are useful for the treatment ofchronic underweight, post-operative conditions, debilitating conditions,and the like. These novel steroids are administered by the usualpharmaceutically acceptable routes, such as orally, at dosages of fromabout 0.01 mg. to about 1.0 mg. per kilogram of body weight of theanimal subject.

The present novel steroids of Formula I, wherein R is hydrogen, andFormula H, exhibit estrogenic activity and accordingly are useful infertility control and for the treatment of amenorrhea, osteoporosis andlike conditions. These novel steroids are administered in the usualpharmaceutically acceptable routes, such as orally, at dosages of fromabout 0.01 mg. to about 1.0 mg. per kilogram of body weight of theanimal subject.

The present compounds are administered as solids in the form of pills,pellets, powders, capsules, and the like, or as liquids in the form ofsolutions (aqueous or non-aqueous), syrups, suspensions, and the like.

The 17a aza-D-homosteroids[17,17a-e]tetrazoles, the present novelcompounds 'of Formulas I and II, are prepared from the correspondingstarting 17-ketoxime steroids by means of the present novel process,which can be illustrated by the following reaction sequence:

N OH I |TO E N: N: i i 1, i

wherein R is hydrogen or methyl; and R is alkoxy or a conventionalhydrolyzable ester.

The 17a-aza D homo-estrano[17,17a-e]tetrazole and 17a-aza Dhomo-androstano[17,17a-e]tetrazole derivatives of the compounds ofFormula B are prepared from the corresponding estrane-l7-one oxime andandrostane- 17-one oxime derivatives, the compounds of Formula A. The17a-aza D homoestra-1,3,5(10)-triene[17,17a-e] tetrazole derivatives,the compounds of Formula D, are prepared from the correspondingestra-1,3,5(10)triene 17-one oxime derivatives, the compounds of FormulaC.

According to the present novel process, the compounds of Formulas B andD are prepared by treating the starting 17-ketoxime steroids, thecorresponding compounds of Formulas A and C, with hydrazoic acid in aninert, nonaqueous, organic solvent. The reaction is carried out attemperatures between 10 C. and 50 C., preferably at about roomtemperature. At least one molar equivalent of hydrazoic acid is used permolar equivalent of l7-ketoxime starting steroid. Preferably, two ormore molar equivalents of hydrazoic acid are used. Typical inert,organic solvents that are used in the present novel process includehydrocarbons, such as benzene, toluene, cyclohexane, hexane, iso-octane,and the like; and halogenated hydrocarbons, such as methylene chloride,chloroform, dichloroethane, and the like.

The product steroid tetrazole is isolated by conventional techniques.For example, the reaction mixture is diluted with Water, extracted witha water-immiscible inert, organic solvent, and chromatographed.

The hydrazoic acid is prepared by treating an azide salt with at leastone H+ equivalent of a strong acidsuch as sulfuric acid, chlorosulfonicacid, or the like. Preferably, two or more H+ equivalents of a strongacid are employed. The reaction is conducted in an inert, organicsolvent; typical inert, organic solvents include hydrocarbons, such asbenzene, hexane, and the like; and

' halogenated hydrocarbons, such as chloroform, ethylene chloride,trichloroethane, and the like. Optionally, the reaction is conductedunder an inert gas atmosphere, such as under a nitrogen gas atmosphere.Typical azide salts employed include lithium azide, sodium azide,potassium azide, calcium azide, lead azide, silver azide, ammonia azide,and the like; sodium azide is the preferred azide salt.

In the preferred embodiment of the present invention, the hydrazoic acidis prepared in situ prior to the introduction of the 17-oximino steroid.

The starting 17-ketoxime steroids that can be employed in the presentnovel process are not limited to those compounds of Formulas A and C.l7-ketoxime steroids substituted at other positions can also beemployed. For example, steroids substituted at positions C-1, 2, 3, 4,5, 6, 7, 9, 11, 12, 14, 15, 16, 18 and/or 19 with amino, fluoro, chloro,bromo, hydroxy, alkoxy, conventional hydrolyzable esters, alkyl,methylene groups and the like can also be employed. Moreover, thesteroid can be substituted with methylene groups bridging positionsC1,2, C-6,7, Cl5,16, and the like. Groups that are attacked by hydrazoicacid obviously cannot be present on the steroid nucleus. Accordingly,the steroid cannot be substituted with keto groups, carboxylic groups,carbonyl groups, nitrile groups, and the like.

The novel compounds of Formula B are subjected to further chemicalprocesses to obtain the novel compounds of Formula I. For example, thecompounds of Formula B can be hydrolyzed via conventional hydrolysismeans to obtain the 3-hydroxy derivatives. These hydroxy derivatives canbe etherified by conventional techniques, such as by treatment withalkali metal hydride and an alkyl halide, Z-dihydrofuranyl halide orZ-dihydropyranyl halide. The hydroxy derivatives can be selectivelyoxidized by treatment with 8 N chromic acid in acetone or chromiumtrioxide in glacial acetic acid to afford the corresponding 3-ketoderivatives. The A -3-keto derivatives are prepared from thecorresponding 3-keto derivatives by conventional techniques; such as byselectively brominating the 3-keto derivative at positions C-2 and C4,and then selectively debrominating the resulting 3- keto-2,4-dibromoderivative at the C-2 position with a molar equivalent of chromousacetate and then dehydrobrominating with a carbonate salt. The thusobtained A 3-keto derivative can be selectively reduced with lithiumaluminum hydride in tetrahydrofuran to obtain the corresponding3fi-hydroxy-A derivative. The thus obtained hydroxy derivative can beetherified by the aforementioned processes or they can be esterified byconventional methods; for example, by treatment with the acid anhydridesof hydrocarbon carboxylic acids in the presence of an acid catalyst.

The novel compounds of Formula D are subjected to further chemicaltransformations to afford the novel compounds of Formula II. Forexample, the novel compounds of Formula D in which R is alkoxy can behydrolyzed by conventional methods, such as by refluxing in an aqueous48% hydrogen bromide acetic acid solution to alford the corresponding3-hydroxy derivative. The latter can be etherified as described above,or esterified by treatment with an acid chloride of a hydrocarboncarboxylic acid, or with an acid anhydride of a hydrocarbon carboxylicacid in the presence of an acid catalyst.

The following examples are included to further illustrate the presentinvention and are not limitations of the claimed invention.

PREPARATION 1 A solution of 2 g. of 5a-androstan-17-one in ml. ethanolwas refluxed for 2 hours with a mixture of 0.9 g.hydroxylamine-hydrochloride, 1.07 g. sodium acetate and 28 ml. ethanol.

Evaporaation of the solvent and extraction with ethyl acetate yields5u-androstan-17-one oxime. The product is recrystallized from acetone.

Similarly, 3fl-acetoxy-5a-androstan-17-one oxime and3-methoxyestra-1,3,5(10)-trien 17 one oxime are prepared from thecorresponding 17-keto steroids.

EXAMPLE 1 To 585 mg. of sodium azide suspended in 10 ml. ethylenechloride, 2.7 ml. of chlorosulfonic acid are slowly added. The mixtureis stirred for one hour and then an additional 585 mg. of sodium azideare added. After 15 minutes a solution of 1.5 g. of 5a-androstan-17-oneoxime in 20 ml. ethylene chloride is slowly added and the reactionmixture is stirred at room temperature for two hours. The reactionmixture is diluted with water and extracted with ethyl acetate; thecombined extracts are evaporated and the residue is chromatographed over150 g. of chromatographic magnesium silicate (Florisil, 15.5% MgO, SiO0.5% Nat- 80 eluting with a mixture of hexanezethyl acetate (8:2). Thefraction containing 17aaza-D-homo 5a androstano[17,17a-e]tetrazole isidentified by nuclear magnetic resonance: 0.81 p.p.m. (19-H); 1.36p.p.m. 18-H). The product is recrystallized from methylenechloridezhexane.

Similarly, 17a aza-D-homo-5a-estrano[17,l7a-e]tetrazole is prepared from5u-estran-17-one oxime.

EXAMPLE 2 To a stirred suspension of 6 g. sodium azide in ml. ethylenechloride, 18 ml. of chlorosulfonic acid are added dropwise. After 1 houran additional 6 g. of sodium azide are added; 16 minutes later asolution of 10 g. of 35- acetoxy-5a-androstane-17-one oxime in ml.ethylene chloride is slowly added. The reaction mixture is stirred atroom temperature for 2 hours and then worked up by addition of water andextracted with methylene chloride. The combined extracts arechromatographed on chromographic magnesium silicate eluting withhexane-ethyl acetate (65:35); the fraction containing35-acetoxy-17aaza-D-homo 5a androstano[17,17a-e]tetrazole is identifiedby nuclear magnetic resonance: 0.86 p.p.m. 19-H; 1.36 ppm. 18-H; 2.0p.p.m., 3B-acetoxy. The product is recrystallized from methylenechloride-diethyl ether.

By employing 3/8-acetoxy-5a-estran-17-one oxime or 3,8-methoxy--estran17 one oxime as the l7-oximino starting material in the above process,3p-acetoxy-17aaza-D-homo-5m-estrano[17,17a-e]tetrazole or 3fi-methoxy-3B-methoxy-5a-estran 17 one oxime as the 17-oximino is obtained.

EXAMPLE 3 Three grams of3fi-acetoxy-17a-aza-D-homo-5a-androstano[l7,17a-e]tetrazole ishydrolyzed in 90 ml. of a 1% potassium hydroxide methanol solution atroom temperature. The hydrolysis is conducted under a nitrogenatmosphere for 18 hours. The reaction mixture is extracted Withmethylene chloride after being diluted with 150 ml. of water. Theextracts are combined, neutralized by the addition of dilutehydrochloric acid, washed with water, filtered, dried over sodiumsulfate, filtered and evaporated to give SB-hydroxy 17a aza D-homo-5aandrostano 17, 17a-e] tetrazole.

Likewise, 3 ,8 hydroxy-17a-aza-D-homo-5a-estrano[l7, 17a-e]tetrazole isprepared from 3fl-acetoxy-17a-aza-D- homo- Saestrano[17,17a-e1tetrazolevia the above hydrolysis.

EXAMPLE 4 To a cooled mixture (8 C.) of 3 g. of 3,8-hydroxy- 17a-aza-D-homo 5a androstano[17,17a-e1tetrazole and 200 ml. of acetone, 3ml. of 8 N chromic acid are slowly added with stirring. After theaddition, the resulting reaction mixture is stirred for an additional 45minutes; then an excess of aqueous sodium bisulfite is added. Theresulting mixture is extracted with methylene chloride; the extracts arecombined, washed to neutrality, dried over sodium sulfate, filtered andevaporated to aiford 3-oxo- 17a-aza-D-homo-5a-androstano[17,17a e]tetrazole. The product is recrystallized from methylene chride:hexane.

Similarly, 3-oxo-l7a-aza-D-homo-5a-estrano[17,17a-e1- tetrazole isprepared from 3fl-hydroxy-17a-aza-D-homo- 5a-estrano[l7,17a-e]tetrazoleby means of the above selective oxidation process.

EXAMPLE 5 A solution of 2 g. of 3-oxo-17a-aza-D-homoandrost-4-eno[l7,l7a-e]tetrazole in 75 ml. acetic acid is treated dropwise with1.92 g. of bromine in 6.2 ml. acetic acid. Three drops of a saturatedsolution of hydrogen bromide in acetic acid are added and the mixturestirred for 18 hours. The reaction mixture is then poured into water;the resulting precipitated solid is extracted with methylene chloride.The combined extracts are washed to neutrality, dried and evaporated invacuo, to yield 2,4-dibromo-3-oxo-17a-azaD-homoandrostano[17,17a-e]tetrazole. The 2,4-dibromo product is added toa solution of 75 ml. of acetic acid and 18 m1. of chloroform. Theresulting mixture is added to 5.3 g. of powdered chromous acetate undera carbon dioxide atmosphere. The resulting mixture is stirred for 10minutes, then air is bubbled through the flask to oxidize the excess ofchromous acetate. The mixture is then poured into cold water, extractedwith methylene chloride, washed several times with water, dried andevaporated in vacuo. The resulting residue is dissolved in 6 ml.dimethyl acetamide and added to a boiling suspension of 0.8 g. ofcalcium carbonate in 18 ml. dimethyl acetamide under a stream ofnitrogen. After minutes the mixture is cooled, poured into water andextracted With methylene chloride, then washed with a 2% solution ofhydrochloric acid and finally with water to neutrality. The residue ispurified by preparative thin-layer chromatography to yield 3-oxo-17a-aza-D-homoandrost-4-eno 17,17a-e] tetrazole.

Similarly, 3 oxo-l7a-aza-D-homoestr-4-eno[17,17a-e]- tetrazole isprepared from 3-oxo-17aaza-D-hom0-.5aestrano[17,l7a-e]tetrazole via theabove selective dehydrogenation process.

EXAMPLE 6 A solution of 1 g. of 3-oxo-l7a-aza-D homoandrost-4-eno[17,17a-e]tetrazole in 50 ml. of tetrahydrofuran is added over a 30minute period to a stirred suspension of 1 g. lithium aluminum hydridein 50 ml. of anhydrous tetrahydrofuran and this mixture is heated atreflux for EXAMPLE 7 A solution of 32.6 g. of3/3-hydroxy-l7a-aza-D-homoandrostan-4-eno[l7,17a-e]tetrazole in 30 ml.of benzene is heated to reflux and about 2 ml. removed by distillationto eliminate moisture. The mixture is cooled to room temperature and 4.8g. of sodium hydride are added, followed by the dropwise addition of19.0 g. of methyl bromide in 10 ml. of benzene over a period of 20minutes. The mixture is allowed to reflux for 20 hours after which timethe precipitate of sodium bromide is removed by filtration and theorganic phase dried and evaporated to yield 3 ,8methoxy-17a-aza-D-homoandrostano-4-eno[17,- 17a-e]tetrazole which isfurther purified upon recrystallization from pentane.

By employing ethyl bromide, isopropyl bromide and cyclopentyl bromide inplace of methyl bromide in the above etherification process thefollowing compounds are respectively obtained:

3fi-ethoxy-17a-aza-D-homoandrostan-4-eno[ 17,17a-e] tetrazole,

3/3-isopropoxy-17a-aza-D-homoandrostan-4-eno[17,17a-

e] tetrazole, and

3 8-cyclopentoxy-17a-aza-D-homoandrostan-4-eno[17,17a-

e] tetrazole.

3 3-methoxy-l7a-aza-D-homoestr 4 eno[17,17a-e]tetrazole is prepared byemploying 3/3-hydroxy-17a-aza-D- homoestr-4-eno[17,l7a-e]tetrazole inthe above process.

EXAMPLE 8 Two milliliters of dihydropyran are added to a solution of 1g. of 3,8-hydroxy-17a-aza-D-homoestr-4-eno- [17a17a-e]tetrazole in 15ml. of benzene. About 1 ml. is removed by distillation to removemoisture and 0.4 g. of p-toluenesulfonyl chloride is added to the cooledsolution. This mixture is allowed to stand at room temperature for fourdays, and is then washed with aqueous sodium carbonate solution andwater, dried and evaporated. The residue is chromatographed on neutralalumina, eluting with hexane, to yield3B-tetrahydropyran-Z'-yloxy-17a-aza-D- homoestr-4-eno[l7,l7a-e]tetrazolewhich is recrystallized from pentane.

3B tetrahydrofuran 2 yloxy-17a-aza-D-homoestr-4- eno[17,17a-e]tetrazoleis obtained by employing dihydrofuran in place of dihydropyran in theabove process.

EXAMPLE 9 A mixture of l g. of 3,8-hydroxy-17a-aza-D-homoestr-4-eno[17,17a-e1tetrazole, 4 ml. of pyridine and 2 ml. of aceticanhydride is allowed to stand at room temperature for 15 hours. Themixture is then poured into ice water and the solid which forms iscollected by filtration, washed with water and dried to yield3B-acetoxy-17a-aza-D-homoestr-4-eno[l7,17a-e]tetrazole which may befurther purified through recrystallization from acetone:hexane.

3fi-benzoyloxy 17a aza-D-homoestr-4-eno[17,17a-e]- 7 tetrazole isobtained by employing benzoyl chloride in place of acetic anhydride inthe above process.

EXAMPLE 10 A mixture of 1 g. 3-oxol7a-aza-D-homoestr-4-eno-[17,17a-e1tetrazole, 2 g. of hydrazine hydrate, 1.2 g. of potassiumhydroxide, 1.2 ml. of water and 1.2 ml. of diethylene glycol is heatedfor 45 minutes at reflux, then in an open flask until the temperature ofthe reaction mixture is 200 C., and finally for an additional 2 hours atreflux. The mixture is cooled, Water added and the product isolated byextraction with ether. These extracts are dried over sodium sulfate andevaporated to yield 17a-aza- D-homoestr-4-eno[17,17a-e]tetrazole whichmay be further purified through recrystallization from acetone:hexane.

EXAMPLE 11 To a suspension of 6 g. of sodium azide and 100 ml. ethylenechloride 13 ml. chlorosulfonic acid is added dropwise with stirring.After 1 hour an additional 6 g. of sodium azide was added, and 1-5minutes later, a solution of 10 g. of3-methoxyestra-l,3,5(10)-trien-17-one oxime is added slowly. The mixtureis stirred for 2 hours and then poured into Water; the product isextracted with methylene chloride. The combined extracts are washed toneutrality with Water, dried, filtered and chromatographed onchromatographic magnesium silicate.

Elution with a gradient (95:57:3) hexene:ethyl acetate mixture yielded afraction [identified by NMR 1.4 p.p.m. (IS-H), 3.75 p.p.m. (3OCH 6.6p.p.m. (4-H), 6.8 p.p.m. (2-H); 7.1-7.3 p.p.m., (1H, doublet: J =8c.p.s.)] containing 3-methoxy-17a-aza-D-homoestra-1,3,(l0)-trieno[17,l7a-e]-tetrazole. After the fraction is evaporated, theproduct is recrystallized from methylene chloride ether.

Similarly,

3-acetoxy-17a-azo-D-homoestra- 1, 3 ,5 10 -trieno- [17,17a-e] tetrazole,

3-tetrahydropyran-2-yloxy-17a-aza-D-homoe'stra- 1,3,5( 10 -trieno[17,17a-e] tetrazole,

3-cyclopentoxy-17a-aza-D-homoestra-1,3 ,5 10 -trieno-[17,17a-e]-tetrazole and3-propoxy-17a-aza-D-homoandrosta-1,3,5(10)-trieno- [17,17a-e]tetrazoleare prepared from the corresponding 17-ketoxime steroids.

EXAMPLE 12 A mixture of 3.24 g. of3-methoxy-17a-aza-D-homoestra-l,3,5(10)-trieno[17,17a-e] tetrazole, 50ml. of aqueous 48% hydrogen bromide, and 50 ml. acetic acid is refluxedfor minutes. The cooled mixture is then neutralized by the addition ofaqueous 5% sodium carbonate and extracted with methylene chloride. Thecombined extracts are washed with water, dried over sodium sulfate andevaporated to yield 3-hydroxy-l7a-aza-D-homoe'stra- 1,3,5 10) -trieno17, 17a-e] tetrazole.

EXAMPLE 13 A solution of 1 g. of 3-acetoxy-17a-aza-D-hornoestra- 1,3,510)-trieno[17,17a-e1tetrazole in 50 ml. of methanol is heated at refluxfor 3 hours with a solution of potassium hydroxide in 1 ml. of water.The reaction mixture is then poured into ice Water and the solid whichforms is collected by filtration, Washed with Water to neutrality anddried to yield 3-hydroxy-17a-aza-D-homoestra-1,3,5(10)-trieno[17,17a-e]tetrazole which is recrystallized from methylenechloridezether.

8 What is claimed is: 1. A compound selected from the group having theformula:

in which R is hydrogen, hydroxy, alkoxy having from 1 to 8 carbon atoms,tetrahydrofuran-2'-yloxy, or tetrahydropyran-2'-yloxy; R is methyl; andZ is a car bou-carbon single bond or a carbon-carbon double bond.

2. A compound selected from the group having the formula:

wherein R is the group O or in Which R is hydroxy, methoxy,tetrahydrofuran-2- yloxy, tetrahydropyran-2-yloxy, or acetoxy; R ismethyl; and Z is a carbon-carbon double bond.

3. The compound of Formula 1 according to claim 2 which is3B-hydroxy-l7a-azo D homoandrost-4-eno- [17,17a-e] tetrazole.

4. The compound of Formula I according to claim 2 which is 38-met'hoxy-17a-aza D homoandrost-4-eno- [17, l7a-e] tetrazole.

5. The compound of Formula I according to claim 2 which is3fi-acetoxy-17a-aza D homoandrost-4-eno- [17, l7a-e] tetrazole.

6. The compound of Formula I according to claim 2 which is 3-0xo-17a-azoD homoandrost 4 eno- [17,17a-e]tetrazole.

References Cited UNITED STATES PATENTS 1,599,493 9/1926 Schmidt 2603083,182,069 5/1965 Mechoulam 260-308 3,389,137 6/1968 Mosby 260288 XFOREIGN PATENTS 123,697 7/ 1967 Czechoslovakia.

OTHER REFERENCES Benson, Chem. Review, vol. 41, pp. 1-61, (partic. p.48) (1947).

DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-288 R, 289 AZ, 345.7, 397, 397.3; 424-458

